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Hi to all. I hope you can help me with this question.
I am testing a new experimental compound in mice. After intraperitoneal
administration I can see increases in plasma concentration and a nice
elimination curve. After proper calculations I detected a relatively low
bioavailability (32%). When I tried a subcutaneous injection of the drug at
the same dose I did not find any increases in plasma levels.
Does anybody have any suggestion to increase the bioavailability after sq
injection? What could be the reason to have such a different bioavailability
after administration by those similar routes?
PS: I'm using 9% sucose, 5% DMSO as vehicle.
Thanks
J.-
Jose M Valdivielso
Senior Research Associate
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Mail BCC-104
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"Jose Valdivielso (by way of David_Bourne)" wrote:
>
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> The following message was posted to: PharmPK
>
> Hi to all. I hope you can help me with this question.
> I am testing a new experimental compound in mice. After intraperitoneal
> administration I can see increases in plasma concentration and a nice
> elimination curve. After proper calculations I detected a relatively low
> bioavailability (32%). When I tried a subcutaneous injection of the drug at
> the same dose I did not find any increases in plasma levels.
> Does anybody have any suggestion to increase the bioavailability after sq
> injection? What could be the reason to have such a different bioavailability
> after administration by those similar routes?
>
Simplest explanation is that your 'proper calculations' were
'improper'. Without giving it IV (or IA) then you dont have a
reference for the profile you see after IP.
-
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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[A few replies - db]
From: bangarurk.aaa.drreddys.com
Date: Tue, 23 Jul 2002 11:00:59 +0530
To: david.at.boomer.org
Subject: Re: PharmPK Bioavailability question
Jose:
I hope that you mean to say that the bioavailability was increased after IP
injection compared to original Oral administration, which is possible for
may drugs where absorption through GIT is less and where presystemic
metabolism is involved.
You better see the bioavailability after i.v administration and compare
your values from p.o, i.p, and s.c routes, it will give fairly clear
picture about the absorption and metabolism.
regards,
banagru.rk
---
From: "Doc, Frederic"
Date: Tue, 23 Jul 2002 09:55:20 -0400
To: david.aaa.boomer.org
Subject: RE: PharmPK Bioavailability question
What is the reference route for F calculation ?
Did you expect to have 100% bioavailability after IP dosing ?
My concern is about the choice of your formulation. DMSO is known to
solubilize drugs at a pretty high level. The trouble is that when you put
your DMSO solution in a physiological environment the drug is likely to
precipitate. Then drug particles have to solubilize again to be absorbed.
I don't know your compound but I suggest that you evaluate other ingredients
with less risk of precipitation.
About SC dosing I am not convinced that it can be declared "similar" to the
IP route in the field of absorption. I really think that IP is a much better
route than subcut if we only consider absorption. Absence of plasma levels
should be explained by the precipitation of the active. The subcut
compartment should then be considered as a reservoir releasing at a (very)
slow rate a small amount of active molecules.
I hope this helps,
Frederic
---
From: NTeuscher.-at-.npsp.com
Date: Tue, 23 Jul 2002 08:20:44 -0600
To: david.-at-.boomer.org
Subject: Re: PharmPK Bioavailability question
You need to review your "calculations". Bioavailability is defined as
the percent of a dose given via a non-IV administration that reaches
circulation as compared to the amount of drug in circulation after IV
administration. In other words, you cannot calculate bioavailability
after an IP administration alone. The formula for bioavailability is:
F (bioavailability) = (AUC_ev/AUC_iv)*(Dose_iv/Dose_ev), where
iv=intraveneous and ev=extravascular administration
Good luck!
Nathan Teuscher
Nathan S. Teuscher
Drug Metabolism Scientist
NPS Pharmaceuticals
420 Chipeta Way
Salt Lake City, UT 84108
Email: nteuscher.at.npsp.com
---
From: Jose Valdivielso
Date: Tue, 23 Jul 2002 09:38:36 -0700
To: david.-a-.boomer.org
Subject: Re: PharmPK Re: Bioavailability question
Sorry I did not explain myself clear. I also have the IV data with the
elimination profile (which correlates with the first order quinetics
equation). My question is focused in the differences between ip and sq
profiles. Why after sq injection the drug does not shows up in plasma?
Thank you again
Jose M Valdivielso
Senior Research Associate
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Mail BCC-104
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Thank you for all you kind responses. I really appreciate your help.
My understanding about absorption rate (please correct me if I am wrong) is
that intramuscular, intraperitoneal and subcutaneous are the same, leading
to similar bioavailability rates. That is the reason I got so surprised to
see such a difference with this compound (from 32% ip to 0% sq).
I guess that my problem is that my compound is precipitating, as Frederic
suggested. Could you please give me more information about the 'other
ingredients with less risk of precipitation' you suggest in you e-mail?
Than you again for all your help.
Jose M Valdivielso
Senior Research Associate
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Mail BCC-104
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Jose,
I would agree saying that IM and SC routes are comparable but I think that
there can be significant differences with IP.
First point: my methodology in your case would be to get a solution of the
drug in a pH7.4 buffer with some surfactant addition. The type and amount of
surfactant to be used are animal model dependent. For instance you can't use
any Polysorbate in dogs. But if you dose rodents then you can take up to 5%
of Tween 80 (Polysorbate 80) in your pH 7.4 buffer. This should allow you to
enhance the drug concentration in your solution at a reasonable extent
without any precipitation issue. You should determine your max solubility in
this kind of vehicle and then use a solution at 80% of max solubility.
Second point: I would suggest that you do some kind of prediction of
precipitation by mixing 1:1 your dosing solution with some pH 7.4 buffer. If
the active does not precipitate with your original formulation then you will
have to find out another hypothesis to explain your observation.
Hope this helps.
Regards,
Frédéric
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